Acetazolamide for acute kidney injury in patients undergoing high dose methotrexate therapy: a systematic review and meta-analysis

Urine alkalization is one of the standard treatments to prevent acute kidney injury in patients receiving high-dose methotrexate. Carbonic anhydrase inhibitors are promising adjuvants/substitutes with advantages such as faster urine alkalization time and prevention of fluid overload. However, there is limited and contradictory evidence on its efficacy and safety. We aimed to compare the efficacy and safety of carbonic anhydrase inhibitors to standard treatments in adult patients receiving high-dose methotrexate.

The protocol was registered at PROSPERO (CRD42022352802) in August 2021. We evaluated the use of carbonic anhydrase inhibitors in combination with standard treatment compared to standard treatment alone. We excluded articles irrelevant to the efficacy and safety of acetazolamide in patients receiving high dose methotrexate and/or did not provide sufficient data regarding doses, recruitment criteria, and follow-up period. Two authors performed the data extraction independently.

Among 198 articles retrieved, six observational studies met all eligibility criteria. Four studies with five datasets (totaling 558 patients/cycles) had enough data to be included in the meta-analysis. We independently report the results from the two remaining studies. The results did not show a significant difference between acetazolamide versus standard treatment in acute kidney injury (AKI) rate (OR = 0.79, 95% CI 0.48–1.29, P = 0.34, I² = 0%). Regarding the time to urine pH goal, there was no significant time difference between the two groups (Mean Difference = 0.07, 95% CI − 1.9 to 2.04, P = 0.95, I² = 25%). Furthermore, our meta-analysis showed that acetazolamide did not reduce length of stay (Mean Difference = 0.75, 95% CI − 0.8 to 2.31, P = 0.34, I² = 0%). In one study, the only reported side effect of acetazolamide was hypokalemia (nearly 50% in the acetazolamide group).

This systematic review showed no significant difference between acetazolamide and standard care treatment regarding urine alkalinization time and AKI rate in adult patients receiving high dose methotrexate. We suggest performing a large blinded, randomized, controlled trial to evaluate the potential benefits of this low-cost medication.